Acitretin, an enhancer of alpha-secretase expression, crosses the blood-brain barrier and is not eliminated by P-glycoprotein.
Neurodegener Dis
; 10(1-4): 224-8, 2012.
Article
em En
| MEDLINE
| ID: mdl-22301853
ABSTRACT
BACKGROUND:
ADAM10 (a disintegrin and metalloproteinase 10) has been demonstrated to act as the main physiological α-secretase. Enzymatic activity of the α-secretase on the one hand prevents the formation of toxic Aß peptides and on the other hand promotes the secretion of a neurotrophic and neuroprotective amyloid precursor protein fragment (APPs-α) by cleaving the amyloid precursor protein within its Aß sequence. Enhancement of ADAM10's gene expression may therefore present a valuable therapeutic approach for the treatment of Alzheimer's disease (AD), where Aß peptides are severely involved in the pathogenesis.OBJECTIVE:
In cell culture and in a transgenic mouse model of AD, retinoids led to increased ADAM10 expression and activity. We therefore endeavor to develop a clinical application of synthetic retinoids such as acitretin in AD.METHODS:
The effect of synthetic retinoids on ADAM10 gene expression was analyzed by reporter gene assays in human neuroblastoma cell line SH-SY5Y. Penetrance of acitretin into the murine brain was analyzed by high-performance liquid chromatography. P-glycoprotein (P-gp) double-knockout mice with a deficiency in both isoforms, mdr1a and 1b, were used to analyze a possible role of P-gp-dependent efflux on acitretin distribution.RESULTS:
Acitretin and tamibarotene are both potent activators of ADAM10 promoter activity. Acitretin crosses the murine blood-brain barrier and its level in the mouse brain is not reduced by P-gp.CONCLUSION:
Synthetic retinoids and especially acitretin seem to be ideal candidates to establish an ADAM10-based AD treatment, and therefore have already entered first clinical trials.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Barreira Hematoencefálica
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Regulação da Expressão Gênica
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Acitretina
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Subfamília B de Transportador de Cassetes de Ligação de ATP
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Secretases da Proteína Precursora do Amiloide
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article